Thyroid Hormone Receptor Beta Research Articles

Relative developmental toxicities of pentachloroanisole and pentachlorophenol in a zebrafish model (Danio rerio)

Pentachloroanisole (PCA) and pentachlorophenol (PCP) are chlorinated aromatic compounds that have been found in the environment and in human populations. The objective of this study is to characterize the effects of PCA in comparison to those of PCP on development at environmental relevant levels using a fish model. Zebrafish embryos were exposed to 0.1, 1, 10, 100, 500, 1000μg/L PCA and PCP respectively for 96h. Malformation observation, LC50 testing for survival rate at 96 hours post fertilization (hpf) and EC50 testing for hatching rate at 72 hpf indicated that the developmental toxicity of PCP was about 15 times higher than that of PCA. PCP exposure at 10μg/L resulted in elevated 3, 3′, 5-triiodothyronine (T3) levels and decreased thyroxine (T4) levels, whereas PCA had no effects on T3 or T4 levels. PCP and PCA exposure at 1 and 10μg/L showed possible hyperthyroid effects similar to that of T3, due to increased relative mRNA expression of synapsin I (SYN), iodothyronine deiodinase type III (Dio3), thyroid hormone receptor alpha a (THRαa) and thyroid hormone receptor beta (THRβ), and decreased expression of iodothyronine deiodinase type II (Dio2). The results indicate that both PCA and PCP exposure can cause morphological deformities, possibly affect the timing and coordination of development in the central nervous system, and alter thyroid hormone levels by disrupting thyroid hormone regulating pathways. However, the developmental toxicity of PCA is at least ten times lower than that of PCP. Our results on the relative developmental toxicities of PCA and PCP and the possible underlying mechanisms will be useful to support interpretation of envrionmental concentrations and body burden levels observed in human populations.

Abstract 3273: Genetic variation in obesity-related genes and breast cancer risk in the Seoul Breast Cancer Study

Abstract Many previous association studies have been addressed genetic variations in obesity related genes on breast cancer risk, however, limited consideration of genes and gene-environmental interaction was involved. We investigated the associations of known obesity-related genes on breast cancer risk by comprehensive assessment based on individual SNP analysis and gene-based pathway-analysis. This study was conducted in 1,786 cases and 1,789 controls from Seoul Breast Cancer Study (SEBCS), a multicenter case-control study. The selection of 1,561 candidate obesity-related gene for this study was involved based on GWAS catalog and previous published data associated with obesity. Associations of single-nucleotide polymorphism (SNP) with BMI were assessed by linear regression models under an additive genetic model adjusting for age and disease status to identify genetic loci for obesity. 2,366 BMI-related significant SNPs including additional significant 449 SNPs which independently associated with BMI in our data (p<10-4) were evaluated for the genetic effect on breast cancer risk. Per-allele odds ratio for breast cancer risk was assessed using logistic regression models adjusting for age and 1st family history of breast cancer. Gene-based pathway significance was assessed by the adaptive rank-truncated product (ARTP) method with 1,000 permutations for association between BMI-related genes and breast cancer risk. Among available 227,197 SNPs from candidate genes and additional significant SNPs in SEBCS data, 12,388 SNPs in 890 genes were found to be associated with BMI (p<0.05): 495 genes (55.7%) from GWAS catalog and 281 genes (48.4%) from published candidate genes for obesity were identified, respectively. Rs17804012 in RBFOX1 and rs2014791 in LINC00317 showed the most significant association with BMI (p<5E-6), which observed null association with breast cancer risk. In contrast, the gene-based pathway analysis including less significantly associated genes with BMI (N=644, p<0.05) showed significant association with breast cancer risk (the pathway p=0.003). Especially, the effect of THRB gene on breast cancer risk has highly significant value (p=9E-04) and the association was confined to premenopausal women with BMI above 23.2 (p<0.01). The group of BMI-related genes including THRB was significantly associated with breast cancer risk in pathway analysis and the associations were different depending on the menopausal status and/or BMI levels. Our results suggest that consideration of the complex genetic pathway related to environmental factors might reveal additional breast cancer susceptibility loci. Citation Format: Seokang Chung, Nan Song, Hyuna Sung, Sue K. Park, Wonshik Han, Dong-Young Noh, Sei-Hyun Ahn, Keun-Young Yoo, Daehee Kang, Ji-Yeob Choi. Genetic variation in obesity-related genes and breast cancer risk in the Seoul Breast Cancer Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3273. doi:10.1158/1538-7445.AM2014-3273

Nongenomic, TRβ-dependent, thyroid hormone response gets genetic support.

In his famous 1962 book, The Structure of Scientific Revolutions, Thomas Kuhn observed that scientific fields undergo periodic paradigm shifts, which open up new approaches to understanding that would never have been considered valid before. For example, currently it seems very clear to state that thyroid hormone (T3) exerts its activity directly on gene expression by binding to nuclear receptors, which are ligand-dependent transcription factors. However, during the 1970s, this view was iconoclastic because hormones were believed to signal only at the cell surface by binding to membrane receptors. However, the cloning of a first gene, now called THRA, which encodes the thyroid hormone receptor (TR)1 nuclear receptor (1) followed by the in vitro characterization of the receptor, definitely established the existence of the nuclear pathway for T3 action, also called the genomic pathway. This was followed by the cloning of the THRB gene, a paralog of THRA, which encodes two other nuclear receptors, TR 1 and TR 2. These two receptors, collectively called TR , differ at their N terminus but both display high similarities with TR 1. Interestingly, due to variations in promoter usage, splicing, and translation initiation THRA was later found to encode a number of other proteins, which do not act as nuclear receptors and whose functions still remain uncertain. Thus, the cloning of THRA and THRB established a new paradigm that demonstrated that some hormones like T3 directly bind transcription factors in the cell nucleusand regulate target gene transcription in contrast to peptide hormones that bind to cell membrane receptors. Nevertheless, a nonnuclear action of T3 has never been ruled out. Some feel that the broad spectrum of physiological functions of T3 would better fit with the existence of more than one mode of action. Importantly, some responses to T3, such as the regulation of movement of ions, sugars, and amino acids, are probably too rapid to be compatible with the time needed for RNA synthesis. Over the years, many different studies have illustrated the possibility for a rapid response and several alternative pathways, called nongenomic pathways for T3 action have been proposed (reviewed in reference 2). This term, however, is confusing because some of the proposed pathways ultimately result in the transcriptional activation of nuclear (3) or mitochondrial (4) genes. Furthermore, the accumulation of in vitro data based on biochemistry and cell culture is not sufficient to demonstrate the developmental or a physiological relevance of the nongenomic pathways, and the matter remains highly controversial. The main weakness of most of these studies is that they lack genetic support. Most importantly, THRA/THRB knockout mice devoid of T3 nuclear receptors have been produced 15 years ago (5, 6), and no residual response to T3 stimulation has been reported in these mice up to now. Therefore, if alternate T3 signaling pathways exist, they probably require the presence of some of the THRA or THRB gene products. If this assumption is correct, the distinction between genomic and nongenomic pathways by genetic means becomes problematic. Among the proposed nongenomic pathways, one relies on a direct interaction between TR and phosphatidylinositol 3-kinase (PI3K). This nongenomic action is suggested to explain the presence of follicular thyroid carcinoma in mice with a frame-shift mutation in the TR C-terminal helix of TR . This so-called TR PV mutant

Thyroid hormone receptors and resistance to thyroid hormone disorders.

Thyroid hormone action is predominantly mediated by thyroid hormone receptors (THRs), which are encoded by the thyroid hormone receptor α (THRA) and thyroid hormone receptor β (THRB) genes. Patients with mutations in THRB present with resistance to thyroid hormone β (RTHβ), which is a disorder characterized by elevated levels of thyroid hormone, normal or elevated levels of TSH and goitre. Mechanistic insights about the contributions of THRβ to various processes, including colour vision, development of the cochlea and the cerebellum, and normal functioning of the adult liver and heart, have been obtained by either introducing human THRB mutations into mice or by deletion of the mouse Thrb gene. The introduction of the same mutations that mimic human THRβ alterations into the mouse Thra and Thrb genes resulted in distinct phenotypes, which suggests that THRA and THRB might have non-overlapping functions in human physiology. These studies also suggested that THRA mutations might not be lethal. Seven patients with mutations in THRα have since been described. These patients have RTHα and presented with major abnormalities in growth and gastrointestinal function. The hypothalamic-pituitary-thyroid axis in these individuals is minimally affected, which suggests that the central T3 feedback loop is not impaired in patients with RTHα, in stark contrast to patients with RTHβ.

Effects of water temperature on perchlorate toxicity to the thyroid and reproductive system of Oryzias latipes

Water temperature is expected to increase in many parts of the world due to global climate change. The change in water temperature may affect ecosystems through alterations of the chemical properties or by affecting the susceptibility of organisms. Perchlorate can disrupt thyroid function of an organism by inhibiting iodide uptake. In the present study, the effect of water temperature on perchlorate toxicity was evaluated using Japanese medaka (Oryzias latipes). Pairs of adult medaka fish were exposed to a sublethal concentration of sodium perchlorate (100mg/L) and a control, at a ‘low’ (26°C), ‘medium’ (29°C) or ‘high’ water temperature (33°C) for seven days. The effects of the water temperature on reproduction, thyroid hormones and cortisol concentrations were determined. Transcription of several genes related to thyroid function and stress were also investigated. Significant down-regulation of thyroid hormone receptor alpha (THR-α) and beta (THR-β) transcripts and up-regulation of deiodinase 2 (DIO2) transcripts were observed in the fish exposed to perchlorate. Thyroxine (T4) concentrations were decreased, while triiodothyronine (T3) levels remained constant following exposure to perchlorate, and this effect became more pronounced under the high water temperature conditions (33°C). Up-regulation of the DIO2 gene may explain these observations. The total number of spawned eggs decreased slightly as the water temperature increased, and this reduction became significant when fish were exposed to perchlorate. Our observations indicate that exposure to perchlorate could affect thyroid function and overall reproductive fitness, and these effects could be aggravated under high water temperatures.

Resistance to thyroid hormone due to mutations in the THRB gene impairs bone mass and affects calcium and phosphorus homeostasis

ContextResistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone, which is usually due to mutations in the thyroid hormone receptor β gene (THRB). Few studies have been conducted to investigate bone and mineral metabolism in RTH. ObjectiveThe objective of the study was to evaluate the clinical and biochemical parameters related to bone and mineral metabolism in RTH due to mutations in the THRB gene (RTHβ). Design and participantsWe conducted a cross-sectional study on 14 patients with RTHβ (RTHG), eight adults and six children, and 24 control subjects (CG). OutcomesSerum measures included total calcium (TCa), inorganic phosphate (iP), alkaline phosphatase (AP), parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), osteocalcin (OC), carboxyterminal telopeptide (CTX), and fibroblast growth factor 23 (FGF-23). We estimated the renal threshold phosphate concentration (TmPO4/GFR) and assessed bone mass using dual X-ray absorptiometry. ResultsAdults and children with RTH showed higher serum levels of TCa than controls (P=.029 and, P=.018 respectively). However, only children with RTH exhibited lower serum levels of iP than controls (P=.048). FGF-23 was higher in RTHβ children (P=.04). RTHβ adults had lower whole-body (P=.01) and lumbar spine (P=.01) bone mineral density than control subjects. The same pattern was observed when the results were expressed as Z-scores between groups, with a lower value in RTHG than in CG for the lumbar spine of adults (P=.03). No difference was observed between groups in PTH, 25OHD, AP, OC, and CTX. ConclusionBiochemical abnormalities are seen in children with RTH (Low iP, high FGF23), while high calcium (with normal UCa) is seen in RTH subjects of all ages, and later on, in adult life, low BMD is seen. Considering that the TRα1 isoform is the predominant TR in the skeleton, we hypothesize that probably these patients may exhibit enhanced calcium flux from bone to circulation. Our data represent a challenge for new studies to unveil the control of calcium and phosphorus homeostasis and fracture risk in these patients.

Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis.

The hypothalamus-pituitary-thyroid (HPT) axis represents a classical example of an endocrine feedback loop. This review discusses dynamic changes in HPT axis setpoint regulation, identifying their molecular and cellular determinants, and speculates about their functional role. Hypothalamic thyrotropin-releasing hormone neurons were identified as key components of thyroid hormone (TH) setpoint regulation already in the 1980s, and this was followed by the demonstration of a pivotal role for the thyroid hormone receptor beta in negative feedback of TH on the hypothalamic and pituitary level. Gradually, the concept emerged of the HPT axis setpoint as a fixed entity, aiming at a particular TH serum concentration. However, TH serum concentrations appear to be variable and highly responsive to physiological and pathophysiological environmental factors, including the availability or absence of food, inflammation and clock time. During food deprivation and inflammation, TH serum concentrations decrease without a concomitant rise in serum TSH, reflecting a deviation from negative feedback regulation in the HPT axis. Surprisingly, TH action in peripheral organs in these conditions cannot be simply predicted by decreased serum TH concentrations. Instead, diverse environmental stimuli have differential effects on local TH metabolism, e.g. in liver and muscle, occurring quite independently from decreased TH serum concentrations. The net effect of these differential local changes is probably a major determinant of TH action at the tissue level. In sum, hypothalamic HPT axis setpoint regulation as well as TH metabolism at the peripheral organ level is flexible and dynamic, and may adapt the organism in an optimal way to a range of environmental challenges.

Alteration of thyroid hormone levels and related gene expression in Chinese rare minnow larvae exposed to mercury chloride

Mercury is a prominent environmental contaminant that causes endocrine disorder to human and other organisms. But little is known about the response of the thyroid functions and hypothalamic–pituitary–thyroid (HPT) axis to mercury in teleosts and the few studies that are available have not yielded consistent results. In this study, expression profiles of corticotropin-releasing hormone (crh), thyroid stimulating hormone beta (tshβ), solute carrier family 5 (sodium iodide symporter) member 5 (slc5a5), thyroglobulin (tg), thyroid hormone receptor alpha (trα) and thyroid hormone receptor beta (trβ) genes were determined in whole-body of Chinese rare minnow (Gobiocypris rarus) larvae after exposure to different levels of Hg2+ (0, 0.1 and 0.3mg/l) for 4 days, as well as the thyroid hormones (THs) levels. Moreover, the 96-h lethal concentration of Hg2+ on rare minnow larvae was determined as 0.32mg/l. The results showed that crh, tg, trα and trβ mRNA levels were significantly up-regulated in the larvae, but the gene expression of tshβ and slc5a5 was not significantly changed in our study. Besides, the THs levels increased in the whole-body of fish, especially the thyroxine (T4) level. The above results indicated that Hg2+ could alter some genes expression in the HPT axis which could be used as the potential biomarkers for evaluating the environmental Hg2+-induced stress in fish.

Reduced effects of thyroid hormone on gene expression and metamorphosis in a paedomorphic plethodontid salamander.

It has been over a century since Gudernatsch (1912, Wilhelm Roux Arch Entwickl Mech Org 35:457-483) demonstrated that mammalian thyroid gland extracts can stimulate tadpole metamorphosis. Despite the tremendous developmental diversity of amphibians, mechanisms of metamorphosis have mostly been studied in a few model systems. This limits our understanding of the processes that influence the evolution of developmental aberrations. Here we isolated thyroid hormone receptors alpha (TRα) and beta (TRβ) from Oklahoma salamanders (Eurycea tynerensis), which exhibit permanently aquatic (paedomorphic) or biphasic (metamorphic) developmental modes in different populations. We found that TRα and TRβ were upregulated by thyroid hormone (T3 ) in tail tissues of larvae from metamorphic populations, but basal levels of TR expression and T3 responsiveness were reduced in larvae from paedomorphic populations. Likewise, we found that T3 treatment resulted in complete loss of larval epibranchials in larvae from metamorphic populations, but little to no epibranchial remodeling occurred in larvae from paedomorphic populations over the same duration. This is the first study to directly demonstrate reduced gene expression and metamorphic responses to T3 in a paedomorphic plethodontid compared to metamorphic conspecifics, and the first salamander system to show differential expression of thyroid hormone receptors associated with alternative developmental patterns.

Effects of glyphosate-based herbicides on survival, development, growth and sex ratios of wood frog (Lithobates sylvaticus) tadpoles. II: Agriculturally relevant exposures to Roundup WeatherMax® and Vision® under laboratory conditions

Glyphosate-based herbicides are currently the most commonly used herbicides in the world. They have been shown to affect survival, growth, development and sexual differentiation of tadpoles under chronic laboratory exposures but this has not been investigated under more environmentally realistic conditions. The purpose of this study is (1) to determine if an agriculturally relevant exposure to Roundup WeatherMax®, a relatively new and understudied formulation, influences the development of wood frog tadpoles (Lithobates sylvaticus) through effects on the mRNA levels of genes involved in the control of metamorphosis; (2) to compare results to the well-studied Vision® formulation (containing the isopropylamine salt of glyphosate [IPA] and polyethoxylated tallowamine [POEA] surfactant) and to determine which ingredient(s) in the formulations are responsible for potential effects on development; and (3) to compare results to recent field studies that used a similar experimental design. In the present laboratory study, wood frog tadpoles were exposed to an agriculturally relevant application (i.e., two pulses) of Roundup WeatherMax® and Vision® herbicides as well as the active ingredient (IPA) and the POEA surfactant of Vision®. Survival, development, growth, sex ratios and mRNA levels of genes involved in tadpole metamorphosis were measured. Results show that Roundup WeatherMax® (2.89mg acid equivalent (a.e.)/L) caused 100% mortality after the first pulse. Tadpoles treated with a lower concentration of Roundup WeatherMax® (0.21mg a.e./L) as well as Vision® (2.89mg a.e./L), IPA and POEA had an increased condition factor (based on length and weight measures in the tadpoles) relative to controls at Gosner stage (Gs) 36/38. At Gs42, tadpoles treated with IPA and POEA had a decreased condition factor. Also at Gs42, the effect on condition factor was dependent on the sex of tadpoles and significant treatment effects were only detected in males. In most cases, treatment reduced the normal mRNA increase of key genes controlling development in tadpoles between Gs37 and Gs42, such as genes encoding thyroid hormone receptor beta in brain, glucocorticoid receptor in tail and deiodinase enzyme in brain and tail. We conclude that glyphosate-based herbicides have the potential to alter mRNA profiles during metamorphosis. However, studies in natural systems have yet to replicate these negative effects, which highlight the need for more ecologically relevant studies for risk assessment.

Epigenetic regulation of thyroid hormone receptor beta in renal cancer.

Thyroid hormone receptor beta (THRB) gene is commonly deregulated in cancers and, as strengthened by animal models, postulated to play a tumor-suppressive role. Our previous studies revealed downregulation of THRB in clear cell renal cell carcinoma (ccRCC), but the culpable mechanisms have not been fully elucidated. Since epigenetic regulation is a common mechanism influencing the expression of tumor suppressors, we hypothesized that downregulation of THRB in renal cancer results from epigenetic aberrances, including CpG methylation and microRNA-dependent silencing. Our study revealed that ccRCC tumors exhibited a 56% decrease in THRB and a 37% increase in DNA methyltransferase 1 (DNMT1) expression when compared with paired non-neoplastic control samples. However, THRB CpG methylation analysis performed using BSP, SNaPshot and MSP-PCR consistently revealed no changes in methylation patterns between matched tumor and control samples. In silico analysis resulted in identification of four microRNAs (miR-155, miR-425, miR-592, and miR-599) as potentially targeting THRB transcript. Luciferase assay showed direct binding of miR-155 and miR-425 to 3′UTR of THRB, and subsequent in vivo analyses revealed that transfection of UOK171 cell line with synthetic miR-155 or miR-425 resulted in decreased expression of endogenous TRHB by 22% and 64%, respectively. Finally, real-time PCR analysis showed significant upregulation of miR-155 (354%) and miR-425 (162%) in ccRCC when compared with matched controls. Moreover, microRNA levels were negatively correlated with the amount of THRB transcript in tissue samples. We conclude that CpG methylation is not the major mechanism contributing to decreased THRB expression in ccRCC. In contrast, THRB is targeted by microRNAs miR-155 and miR-425, whose increased expression may be responsible for downregulation of THRB in ccRCC tumors.

Thyroid Hormone Signaling In Vivo Requires a Balance between Coactivators and Corepressors

Resistance to thyroid hormone (RTH), a human syndrome, is characterized by high thyroid hormone (TH) and thyroid-stimulating hormone (TSH) levels. Mice with mutations in the thyroid hormone receptor beta (TRβ) gene that cannot bind steroid receptor coactivator 1 (SRC-1) and Src-1(-/-) mice both have phenotypes similar to that of RTH. Conversely, mice expressing a mutant nuclear corepressor 1 (Ncor1) allele that cannot interact with TRβ, termed NCoRΔID, have low TH levels and normal TSH. We hypothesized that Src-1(-/-) mice have RTH due to unopposed corepressor action. To test this, we crossed NCoRΔID and Src-1(-/-) mice to create mice deficient for coregulator action in all cell types. Remarkably, NCoR(ΔID/ΔID) Src-1(-/-) mice have normal TH and TSH levels and are triiodothryonine (T(3)) sensitive at the level of the pituitary. Although absence of SRC-1 prevented T(3) activation of key hepatic gene targets, NCoR(ΔID/ΔID) Src-1(-/-) mice reacquired hepatic T(3) sensitivity. Using in vivo chromatin immunoprecipitation assays (ChIP) for the related coactivator SRC-2, we found enhanced SRC-2 recruitment to TR-binding regions of genes in NCoR(ΔID/ΔID) Src-1(-/-) mice, suggesting that SRC-2 is responsible for T(3) sensitivity in the absence of NCoR1 and SRC-1. Thus, T(3) targets require a critical balance between NCoR1 and SRC-1. Furthermore, replacement of NCoR1 with NCoRΔID corrects RTH in Src-1(-/-) mice through increased SRC-2 recruitment to T(3) target genes.

THRB (Thyroid Hormone Receptor, Beta)

Review on THRB, with data on DNA/RNA, on the protein encoded and where the gene is implicated.

MicroRNAs 424 and 503 are mediators of the anti-proliferative and anti-invasive action of the thyroid hormone receptor beta.

The thyroid hormone receptors (TRs) mediate tumor suppressive effects in hepatocarcinoma and breast cancer cells. Here we show that incubation of hepatocarcinoma SK-hep1 cells expressing TRb with the thyroid hormone T3 induces transcription of the polycistronic message coding for microRNAs 424 and 503. TRb binds to the promoter region of these miRNAs and T3 induces an exchange of corepressors and coactivators inducing histone acetylation and transcriptional stimulation. We have validated cell cycle components as targets of these miRNAs. Overexpression of miR-424 mimicked the repressive effect of T3 on cell proliferation, growth in suspension, migration and invasion. Knockdown of miR-424 or miR-503 reduced the inhibitory effect of the hormone. T3 increased miR-424 and miR-503 in breast cancer cells expressing TRb, and this induction is also involved in the anti-invasive effects of the hormone. Furthermore, miR-424 or miR-503 depletion enhanced extravasation to the lungs of hepatocarcinoma cells injected in the tail vein of mice. The levels of these miRNAs were reduced in xenograft tumors formed in hypothyroid nude mice that are more invasive. Therefore, miR-424 or miR-503 mediate anti-proliferative and anti-invasive actions of TRb both in cultured cells and in vivo.

Glucose infusion increases mRNA expression of deiodinase 1 & 2, and thyroid hormone receptor β‐1 in a fasting‐adapted mammal (1101.12)

Food deprivation in mammals is typically associated with reduced glucose, thyroid hormone (TH) concentrations and deiodinase (DI) content and activity to suppress metabolism. However, in prolong‐fasted, metabolically active elephant seal pups, the hypothalamic‐pituitary‐thyroid axis (HPT axis), which is responsible for the production of TH, is up‐regulated. The functional relevance of this apparent paradox is unknown and demonstrates variability in the regulation of TH levels, metabolism and function in food‐deprived mammals. To address our hypothesis that increased glucose increases peripheral TH receptor beta‐1 (THrβ‐1) mRNA expression and content in prolong‐fasted pups, we assessed the cellular TH‐mediated response to a glucose challenge by measuring TH profiles during a glucose tolerance test (GTT) and comparing the changes in profiles in early and late fasted pups. THrβ‐1 mRNA expression increased 59% ± 24 and 336% ± 95 by the 60 and 120 minute mark, respectively. Protein expression of THrβ‐1 also increased during the GTT, 40% ± 4 and 80% ± 23 at 60 and 120 minutes, respectively. mRNA expression of DI1 and DI2 increased by the 120 minute time point, 100% ± 34 and 400% ± 63, respectively. The data suggests that cellular TH pathways are responsive to changes in glucose, which in turn maybe regulated by TH. This suggests that the HPT axis is active and functional during prolonged food‐deprivation in metabolically and physically active mammals.Grant Funding Source: Supported by NIH/NHLBI 442606‐RO‐29013

Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism.

Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2, 3), only 3 years after the cloning of the THR genes (4, 5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed TSH, often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced cellular access of the biologically active thyroid hormone, T3, were identified. These are caused by defects of thyroid hormone cell membrane transport (8, 9) and a defect reducing the intracellular metabolism generating T3 from T4 (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.” Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11, 12), we propose using the term “RTH α”, and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20 000 references, only a few related to resistance to thyroid hormone. Table 1. Inheritable Forms of Impaired Sensitivity to Thyroid Hormone

Classification and Proposed Nomenclature for Inherited Defects of Thyroid Hormone Action, Cell Transport, and Metabolism

Resistance to thyroid hormone (RTH) was first described in 1967 (1), and the first mutations in the THRB gene were identified in 1989 (2,3), only three years after the cloning of the THR genes (4,5). The cardinal features of this syndrome of reduced sensitivity to thyroid hormone are elevated serum levels of free thyroid hormone with nonsuppressed thyrotropin (TSH), often with goiter and no clear symptoms and signs of thyrotoxicosis (6). In fact, signs of decreased and increased thyroid hormone action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom, in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH (7), as defined above. In the ensuing years more than 3000 cases have been identified, 80% of which harbored mutations in the THRB gene. More recently, two syndromes with reduced cellular access of the biologically active thyroid hormone, triiodothyronine (T3), were identified. These are caused by defects of thyroid hormone cell membrane transport (8,9) and a defect reducing the intracellular metabolism generating T3 from thyroxine (T4) (10). To accommodate these new findings, it was proposed to broaden the definition of hormone resistance. Thus, the Fifth International Workshop on Resistance to Thyroid Hormone, which took place in Lyon, France, in 2005, saw the introduction of the term “reduced sensitivity to thyroid hormone (RSTH) to encompass all defects that can interfere with the biological activity of a chemically intact thyroid hormone secreted in normal or excessive amounts.” Following the 10th International Workshop on Resistance to Thyroid Hormone and Action that took place in Quebec City, Canada, in 2012, a number of investigators took on the task to develop a nomenclature for inherited forms of impaired sensitivity to thyroid hormone (Table 1). The term “impaired” was to substitute for “reduced” because nascent data indicate that syndromes of increased sensitivity may also exist. We are cognizant that no nomenclature can fit perfectly all aspects of the described syndromes because variability exists. Several aspects were taken into consideration: the already existing nomenclature, new findings, and anticipated putative discoveries. For example, in over 2000 publications “RTH” is used to define a phenotype of congenitally increased free T4 with nonsuppressed TSH, irrespective of the presence or absence of a THRB gene mutation (see non-TR-RTH). In view of the identification of THRA gene mutations that present a distinct phenotype (11,12), we propose using the term “RTH α,” and in new publications to use “RTH β” when a THRB gene mutation is present in association with the RTH phenotype. This allows the naming of new gene defects in individuals with the RTH phenotype. The use of the abbreviation “THR” as a synonym for RTH is discouraged, not only because the hormone is not resistant, but also because this abbreviation is used to denote other circumstances. Indeed, a Medline search using THR yielded over 20,000 references, only a few related to resistance to thyroid hormone. Table 1. Inheritable Forms of Impaired Sensitivity to Thyroid Hormone

Effects of waterborne cadmium on thyroid hormone levels and related gene expression in Chinese rare minnow larvae

Cadmium is a heavy metal abundant in the environment that can induce endocrine disorder and toxicity in aquatic organisms at low levels. However, its effects on the thyroid system in fish are still unclear. In this study, the thyroid hormone (TH) levels and the expression profiles of genes related to hypothalamic– pituitary–thyroid (HPT) axis, including corticotropin-releasing hormone (crh), thyroid stimulating hormone beta (tshβ), solute carrier family 5 (sodium iodide symporter) member 5 (slc5a5), thyroglobulin (tg), thyroid hormone receptor alpha (trα) and thyroid hormone receptor beta (trβ), were determined in whole body of Chinese rare minnow (Gobiocypris rarus) larvae after exposure to different levels of Cd2+ (0, 0.5 and 2.5mg/L) for 4days. And the 96-h lethal concentration of Cd2+ on rare minnow larvae was determined as 2.59mg/L. The results showed that crh, slc5a5, tg and tshβ mRNA levels were significantly up-regulated in the larvae, but the gene expression of trα and trβ was down-regulated in a concentration-dependent manner. Besides, the THs levels decreased in the whole-body of fish, especially the thyroxine (T4) level. The above results indicated that Cd2+ could alter gene expression in the HPT axis that might subsequently contribute to thyroid disruption.

A rare thyroid hormone receptor beta (THRβ) gene mutation in a 15-year-old girl with thyroid hormone resistance syndrome: a case report

IntroductionResistance to thyroid hormone is a rare syndrome, where although the level of thyroid hormone is elevated, the level of thyroid stimulating hormone is not suppressed. The patient in our case report is, to the best of our knowledge, the first with this syndrome identified in Oman.Case presentationIn one Omani family, a 15-year-old girl of Arabian origin was pre-diagnosed with resistance to thyroid hormone. Blood sample was collected and deoxyribonucleic acid was isolated for molecular genetic testing. The results revealed a rare mutation A268G in the gene for thyroid hormone receptor beta. We believe that this mutation is the cause of the pathology in our patient.ConclusionWe report the presence of a rare mutation in the thyroid hormone receptor beta gene for the first time in the Omani population. Due to the rates of consanguinity being high among the Omani population, we are aiming to screen our patient’s family members and provide genetic counseling.

Identification of four novel mutations in the thyroid hormone receptor-β gene in 164 Spanish and 2 Greek patients with resistance to thyroid hormone.

The aim of the study was to describe the clinical, biochemical, and genetic features of a sample of Mediterranean patients with RTH (resistance to thyroid hormone) due to mutations in TRβ (thyroid hormone receptor beta) referred to our institution during the last 15 years. 166 blood samples were received for RTH genetic testing between January 1997 and December 2011. Genetic testing was performed by PCR amplification followed by sequencing of exons 7, 8, 9, and 10. Clinical and biochemical features were obtained from available information sent by referring hospitals. Mutations were identified in 50 patients (29 probands and 21 relatives). 64% were women, and mean ± stdev age at diagnosis among probands was 33.2 ± 20.5 years. The following clinical features were recorded: goiter in 50%, hyperkinetic behavior in 32%, and tachycardia in 29%. Up to 19% of the probands had undergone some type of thyroidal ablative therapy before diagnosis. As for biochemical features, mean ± stdev TSH was 10.2 ± 21.4 mUI/L, and mean ± stdev fT4 was 35.5 ± 10.8 pmol/L. We found four new mutations: p.Phe451Leu, p.Pro452Arg, p.Glu457Gly, and p.Phe459Leu. The clinical and biochemical characteristics of our samples of Mediterranean populations with RTH were similar to those described in the published literature. Interestingly, in our populations we have identified four novel mutations in the TRβ gene.